CN113698404B - Hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide compound with low solvent residue and preparation method thereof - Google Patents

Abstract

The present disclosure relates to a hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide compound with low solvent residue and a method for preparing the same. In particular to (3 aR,5s,6 aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide with low solvent residue and impurity content, a crystal form and a preparation method thereof.

Description

Hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide compound with low solvent residue and preparation method thereof

Technical Field

The disclosure belongs to the technical field of medicines, and in particular relates to a compound (3 aR,5s,6 aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide with low solvent residue and impurity content and a preparation method thereof.

Background

The clinical JAK inhibitor is mainly used for screening therapeutic drugs such as blood system diseases, tumors, rheumatoid arthritis, psoriasis and the like. Currently, a number of JAK inhibitors have entered clinical studies, such as FDA approved Ruxolitinib (Ruxolitinib) for the treatment of hematological disorders and Tofacitinib (Tofacitinib) for gouty arthritis.

WO2013091539 discloses a series of novel JAK kinase inhibitors including the compound (3 ar,5s,6 as) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide. Also WO2014194741 discloses bisulphates of this compound. WO2016054959 and WO2016070697 disclose the I and II forms, respectively, of the bisulfate salt of the compound. CN201780001376.6 discloses a pharmaceutical composition containing the bisulfate salt of the compound. In the prior art, the compound is mostly developed into clinical medicines in the form of salt, and the compound raw material medicines meeting the residual solvent standard of Chinese pharmacopoeia are rarely developed into preparations.

Residual solvents in pharmaceuticals are defined at ICH (international human drug registry and pharmaceutical technology consortium) as organic volatile compounds that are produced or used in the manufacture of bulk drugs or excipients, and which are not completely removed in the process. The guidelines classify the residual solvents according to the degree of hazard and formulate acceptable amounts, i.e., limits, of the residual solvents under conditions that ensure human safety, providing some toxicologically acceptable levels of the residual solvents. According to ICH guidelines, the residual solvents are classified into three types, namely a first type of solvent, a second type of solvent and a third type of solvent. The first type of solvent refers to solvents known to be carcinogenic and strongly suspected of being harmful to humans and the environment, including benzene (2 ppm), carbon tetrachloride (4 ppm), 1, 2-dichloroethane (5 ppm), 1-dichloroethane (8 ppm), and the like. The second type of solvent refers to solvents that are not genotoxic but are carcinogenic to animals, including chloroform (60 ppm), 1, 4-dioxane (380 ppm), dimethylacetamide (1090 ppm), methanol (3000 ppm), methylene chloride (600 ppm), n-hexane (290 ppm), etc. The third type of solvent refers to solvents with low toxicity to human body, including acetone, ethyl acetate, ethanol, pentane, dimethyl sulfoxide, isobutyl acetate, and tributylmethyl ether.

In the preparation of the compound (3 aR,5s,6 aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide, solvents such as methanol, ethanol, acetone, methylene chloride, dimethyl sulfoxide and the like are generally used. However, the compound obtained by the conventional preparation method cannot reach the regulations (methanol is less than or equal to 0.3%, ethanol is less than or equal to 0.5%, dichloromethane is less than or equal to 0.06%, N-hexane is less than or equal to 0.029%, tetrahydrofuran is less than or equal to 0.072%, dimethyl sulfoxide is less than or equal to 0.5%, and N, N-dimethylformamide is less than or equal to 0.088%) about solvent residues in Chinese pharmacopoeia 2015, and particularly, the solvent similar to dimethyl sulfoxide has the characteristics of high boiling point and low volatility and is easy to wrap in solids. Therefore, there is an urgent need in the industry to develop a method for effectively controlling solvent residues in the product to develop a pharmaceutically acceptable (3 ar,5s,6 as) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide compound drug substance.

In addition, in the process of drug development, the content of active ingredients and the content of impurities in the drug directly influence the curative effect and toxic and side effects of the drug. In order to obtain safe and effective medicines, the limit of related substances (impurities) of the medicines is strictly regulated (the impurity D is less than or equal to 0.6 percent) in the Chinese pharmacopoeia 2015,

disclosure of Invention

The present disclosure provides a compound (3 ar,5s,6 as) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide, wherein the mass percent of the organic solvent is less than 2.0%, including 2.0%, 1.90%, 1.80%, 1.70%, 1.60%, 1.50%, 1.40%, 1.30%, 1.20%, 1.10%, 1.00%, 0.90%, 0.80%, 0.70%, 0.60%, 0.50%, 0.40%, 0.30%, 0.20%, 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or less.

In some embodiments, the content of methanol, ethanol, methylene chloride, N-hexane, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide in the compound is less than 0.3%, 0.5%, 0.06%, 0.03%, 0.08%, 0.6%, 0.1%, respectively. In some embodiments, the content of methanol, ethanol, methylene chloride, N-hexane, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide in the compound is less than 0.2%, 0.5%, 0.01%, 0.05%, 0.5%, 0.01%, respectively. In some embodiments, the content of methanol, methylene chloride, n-hexane, tetrahydrofuran in the compound is less than 100ppm, 50ppm, 10ppm, and 10ppm, respectively. In other embodiments, the content of solvents other than methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide in the compound meets the limit specifications of the chinese pharmacopoeia for residual solvents.

In another aspect, some embodiments provide compounds having a process impurity of less than 1%, including 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less, preferably less than 0.6%,

in some embodiments, the compounds described in the present disclosure are present in an amount greater than 97.00%, by way of non-limiting example, greater than 97.00%, 97.10%, 97.20%, 97.30%, 97.40%, 97.50%, 97.60%, 97.70%, 97.80%, 97.90%, 98.00%, 98.10%, 98.20%, 98.30%, 98.40%, 98.50%, 98.52%, 98.54%, 98.56%, 98.58%, 98.60%, 98.62%, 98.64%, 98.66%, 98.68%, 39965%, 98.72%, 98.74%, 98.76%, 98.78%, 98.80%, 98.82%, 98.84%, 98.86%, 98.88%, 98.90%, 98.92%, 98.94%, 98.96%, 98.98%, 99.00%, 99.02%, 99.04%, 99.06%, 99.08%, 99.10%, 99.12% >. 99.14%, 99.16%, 99.18%, 99.20%, 99.22%, 99.24%, 99.26%, 99.28%, 99.30%, 99.32%, 99.34%, 99.36%, 99.38%, 99.40%, 99.42%, 99.44%, 99.46%, 99.48%, 99.50%, 99.52%, 99.54%, 99.56%, 99.58%, 99.60%, 3996%, 99.64%, 99.66%, 99.68%, 99.70%, 99.72%, 99.74%, 99.76%, 99.78%, 99.80%, 99.82%, 99.84%, 99.86%, 99.88%, 99.90%, 99.92%, 99.94%, 99.96%, 99.98%, any number between the two numbers or more, preferably greater than 99.00%.

In another aspect, the compounds of the present disclosure are crystalline in structure. In some embodiments, the compound has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, having characteristic peaks at 9.11, 12.43, 13.54, 15.54, 19.62, 25.85, and 26.99.

In some embodiments, the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 9.11, 10.66, 12.43, 13.54, 15.54, 19.62, 21.04, 25.55, 25.85, and 26.99.

In alternative embodiments, the compound has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, having characteristic peaks at 9.11, 10.66, 12.43, 12.71, 13.54, 15.54, 16.52, 19.62, 21.04, 21.39, 25.55, 25.85, and 26.99.

Further, in alternative embodiments, the compound has characteristic peaks at 9.11, 10.66, 12.43, 12.71, 13.54, 15.54, 16.52, 19.34, 19.62, 21.04, 21.39, 22.88, 25.55, 25.85, and 26.99.

In other embodiments, the compound has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as shown in figure 1.

In other embodiments, the 2 theta angle error range is ± 0.20.

In another aspect, the present disclosure also provides a process for preparing the foregoing compounds, comprising at least one step of crystallization from an organic solvent comprising water.

In some embodiments, the organic solution in the foregoing method contains a solvent (I) that is dimethyl sulfoxide and a solvent (II) selected from C _1-6 At least one of alkyl alcohol, ethyl acetate, water, n-hexane, acetone, isopropyl ether, methyl tertiary butyl ether, acetonitrile, tetrahydrofuran, 1, 4-dioxane or dichloromethane, wherein the C _1-6 The alkyl alcohol is preferably selected from methanol, ethanol, isopropanol.

In some embodiments, the method of preparing the foregoing compounds comprises:

a) Mixing a crude product of a compound (3 aR,5s,6 aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide with a solvent (I), stirring for dissolving or heating for dissolving;

b) Then adding a solvent (II) for crystallization, wherein the solvent (II) is at least one of methanol, ethanol, isopropanol and water, and more preferably ethanol;

c) Adding the solid obtained in the step b) into a solvent (III), stirring and dissolving or heating and dissolving, wherein the solvent (III) is dimethyl sulfoxide;

d) Then adding solvent (IV) for crystallization, wherein the solvent (IV) is preferably a mixed solution of at least one of methanol, ethanol or isopropanol and water.

In some embodiments, the method of preparing the foregoing compounds comprises:

a) Mixing (3 aR,5s,6 aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide and dimethyl sulfoxide, stirring for dissolving or heating for dissolving;

b) Then ethanol is added for crystallization;

c) Adding the solid obtained in the step b) into dimethyl sulfoxide, stirring and dissolving or heating and dissolving;

d) Then adding the mixed solution of ethanol and water for crystallization.

In other embodiments, the method of preparing the foregoing compounds preferably includes a step of slurrying and purifying.

In other embodiments, the process for preparing the aforementioned compounds further comprises the steps of filtration, washing or drying, preferably drying under reduced pressure, at a pressure of < -0.08MPa.

In some embodiments, the volume (ml) of solvent (I) used in the present process is 1 to 50 times the weight (g) of the compound, and may be 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

In other embodiments, the ratio of the volume (ml) used for solvent (I) to the volume (ml) used for solvent (II) in the present process is from 10:1 to 1:10, and can be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10; preferably 1:1 to 1:10..

In other embodiments, the ratio of the volume (ml) used for solvent (III) to the volume (ml) used for solvent (IV) in the present process is from 10:1 to 1:10, and can be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10; preferably 1:1 to 1:10.

In another aspect, the present disclosure also provides a compound prepared by the aforementioned preparation method, wherein the mass percentage of the organic solvent is less than 2%, further wherein the contents of methanol, ethanol, dichloromethane, N-hexane, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide are respectively less than 0.3%, 0.5%, 0.06%, 0.03%, 0.08%, 0.6%, 0.1%.

The present disclosure also provides a pharmaceutical composition comprising the foregoing compound or a compound prepared by the foregoing method, and optionally a pharmaceutical excipient from a pharmaceutically acceptable excipient.

The present disclosure also provides a pharmaceutical composition prepared from the aforementioned compounds and optionally pharmaceutically acceptable excipients.

The present disclosure also provides a method of preparing a pharmaceutical composition comprising the step of mixing the aforementioned compound or a compound prepared by the aforementioned method with a pharmaceutically acceptable excipient.

The present disclosure also provides the use of a compound as described above or a compound prepared by a method as described above or a composition as described above in the manufacture of a medicament for treating or preventing a disease associated with JAK kinase.

The disclosure also provides the use of the foregoing compounds or compounds prepared by the foregoing methods or compositions in the manufacture of a medicament for the treatment or prevention of rheumatic and rheumatoid arthritis.

The "2θ or 2θ angle" described in the present disclosure refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 theta is + -0.20, and can be-0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

The term "differential scanning calorimetric analysis or DSC" as used in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference during the temperature rising or constant temperature of the sample, so as to characterize all physical and chemical changes related to thermal effects, and obtain phase change information of the sample.

The drying temperature in the present disclosure is generally 25℃to 100 ℃, preferably 40℃to 70 ℃, more preferably 45℃to 55 ℃, and can be either normal pressure drying or reduced pressure drying, with a pressure of < -0.08MPa, for a drying time of 5 to 10 hours, preferably 7 to 8 hours.

The numerical values in the present disclosure are data on the determination calculation of the content of the relevant substances, and a certain degree of error is unavoidable. Generally, ±10% all fall within a reasonable error range. There is a degree of variation in error, depending on the context in which it is used, of no more than + -10%, which may be + -9%, + -8%, + -7%, + -6%, + -5%, + -4%, + -3%, + -2% or + -1%, preferably + -5%.

Drawings

Fig. 1: XRPD pattern of crystalline form I of compound (3 ar,5s,6 as) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide.

Detailed Description

The present disclosure will be explained in more detail below with reference to examples or experimental examples, which are only for illustrating technical solutions in the present disclosure, and do not limit the spirit and scope in the present disclosure.

Reagents used in the present disclosure are commercially available.

Test conditions of the instrument used for the experiments in this disclosure:

1. gas chromatography (Gas Chromatography, GC)

Instrument model: agilent 7890B

Detecting objects and corresponding detecting conditions: residual solvents such as methanol, ethanol, acetone, methylene chloride, methyl tertiary butyl ether, n-hexane, ethyl acetate, tetrahydrofuran, ethylene glycol dimethyl ether, toluene and the like. A capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as a fixing solution is used as a chromatographic column (30 m x 0.53mm x 3.0 m); the temperature of the sample inlet is 160 ℃; FID detector temperature 260 ℃; heating program: the initial column temperature is 40 ℃, the temperature is kept for 6min, the temperature is increased to 180 ℃ at 20 ℃/min, and the temperature is kept for 6min; the carrier gas was nitrogen gas at a flow rate of 4.0ml/min with a split ratio of 10:1. Headspace column incubator: 80 ℃; quantitative ring: 90 ℃; a transmission line: 100 ℃; sample balancing: 20min, gc cycle time: 26min; dimethyl sulfoxide (DMSO) was the solvent.

Detecting objects and corresponding detecting conditions: dimethyl sulfoxide (DMSO) residual solvent. Capillary column using polyethylene glycol (or similar polarity) as stationary liquid as chromatographic column

The temperature of the sample inlet is 120 ℃; FID detector temperature 260 ℃; heating program: heating the initial column temperature to 180 ℃ at 10 ℃/min, and keeping for 6min; the carrier gas is nitrogen, the flow rate is 3.0ml/min, and the split ratio is 10:1; sample injection amount: 1 μl;1, 3-dimethyl-2-imidazolidinone (DMI) is the solvent.

2. High Performance Liquid Chromatography (HPLC)

Instrument model: agilent 1260, chromatographic column: XSselect HSS T3 column (4.6X105 mm,3.5 μm); detection wavelength: 218nm; mobile phase: 0.01mol/L potassium dihydrogen phosphate solution is added with 0.1 percent of triethylamine and acetonitrile as mobile phase.

3. X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)

(1) Instrument model: bruker D8 Focus X-ray powder diffractometer

Rays: monochromatic Cu-ka radiation (λ=1.5406)

Scanning mode: θ/2θ, scan range: 2-40 DEG

Voltage: 40KV, current: 40mA

Example 1:

a) 3-methoxy-1, 2, 4-thiadiazol-5-amine 34a (500 mg,3.82 mmol) and phenyl chloroformate 34b (600 mg,3.82 mmol) were dissolved in 20mL of dichloromethane, triethylamine (0.8 mL,5.73 mmol) was added dropwise, and the reaction was completed. The reaction mixture was diluted with water, separated, the aqueous phase was extracted with methylene chloride, the organic phases were combined, dried, filtered, and the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give phenyl 3-methoxy-1, 2, 4-thiadiazol-5-ylcarbamate (200 mg, white solid) as a product in 20.8% yield.

MS m/z(ESI):252.0[M+l]

b) N-methyl-N- ((3 aR,5s,6 a) -octahydrocyclopenta [ c ] pyrrol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride 6a (120 mg,0.47 mmol) was dissolved in 15mL of tetrahydrofuran, phenyl 3-methoxy-1, 2, 4-thiadiazol-5-ylcarbamate (117 m g,0.47 mmol) prepared above was added, and triethylamine (0.13 mL,0.94 mmol) was added dropwise and the mixture was reacted at 60 ℃. Water was added to the reaction solution, extracted with methylene chloride, and the organic phases were combined, washed with saturated sodium chloride solution, dried, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the compound (3 aR,5s,6 aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide crude (50 mg, white solid) (compound a), yield 25.9%, purity 98.5% by HPLC.

MS m/z(ESI):412.9[M-l]

Example 2:

2g of the compound a of the example 1 is taken and refined according to 3 solvent systems in the table 1, namely 16ml of dimethyl sulfoxide is added respectively, the mixture is heated to 45 to 55 ℃ for dissolution, 40ml of acetone, 16ml of water and 32ml of ethanol are added respectively under stirring, stirring and crystallization are carried out, filtration is carried out, and filter cakes are dried in vacuum at 45 to 55 ℃ for 8 hours to obtain 1.5g, 1.9g and 1.86g of solid samples respectively, and the yields are 75.0%, 95.3% and 93.0% respectively. Purity was 99.51%, 98.72% and 99.24%, respectively, as determined by HPLC.

TABLE 1

From the above experiments, it was found that the yield of Compound a was low when DMSO/acetone was purified. The DMSO/water system has high purification yield but lower purity. The yield and purity can reach higher level only by refining with DMSO/ethanol.

Example 3:

into a reaction flask, 4L of tetrahydrofuran was added, while stirring, 373.7g (3.67 mol,4.32 eq) of triethylamine, (229.8 g (0.91 mol,1.07 eq) of phenyl 3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate, 220.0g (0.85 mol,1.0 eq) of N-methyl-N- ((3 aR,5s,6 aS) -octahydrocyclopenta [ c ] pyrrol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine, and then heated to reflux, cooled and filtered. The filter cake is dried in vacuum at 45-55 ℃ to obtain 340.2g of crude product of the solid product compound a, and the purity is 96.36%.

Experimental example 1: 220.0g of crude product of the compound a is taken, 1760ml of dimethyl sulfoxide is added, heating, leaching is carried out after dissolving, filtrate is collected, 3.5L of absolute ethyl alcohol is slowly added under stirring, stirring and leaching are carried out, and filter cake is dried in vacuum for 8h under the condition that the temperature is 45-55 ℃ and the pressure is less than-0.08 MPa, thus obtaining 181.2g of solid product with the purity of 98.69%. The impurity D content was 0.71% by HPLC. The impurity D is not in accordance with the standard of less than or equal to 0.6% specified by the 2015 edition of Chinese pharmacopoeia. The residual solvent contents of methanol, ethanol, methylene chloride, n-hexane, tetrahydrofuran and dimethyl sulfoxide were 0.0073%, 2.2145%, 0.0079%, 0.0003%, 0.0031% and 0.89%, respectively, as determined by GC. According to the regulations of 2015 edition of Chinese pharmacopoeia, methanol is less than or equal to 0.3 percent, ethanol is less than or equal to 0.5 percent, dichloromethane is less than or equal to 0.06 percent, n-hexane is less than or equal to 0.029 percent, tetrahydrofuran is less than or equal to 0.072 percent, and dimethyl sulfoxide is less than or equal to 0.5 percent, wherein the residual solvent of ethanol and dimethyl sulfoxide does not meet the standards of Chinese pharmacopoeia.

Example 4:

experimental example 1: 40.0g of the purified solid sample in experimental example 1 of example 3 was taken and added into a reaction flask, 320ml of dimethyl sulfoxide was added, the mixture was heated, the solution was filtered off with suction, the filtrate was transferred into the reaction flask, the mixture was stirred and heated, 640ml of an absolute ethanol/purified water mixed solvent (volume ratio: 1) was added, and crystallization was carried out with stirring. Suction filtration, filter cake added to 400ml of absolute ethanol/purified water mixed solvent (volume ratio 1:1). Vacuum filtering, vacuum drying the filter cake for 8h at 45-55 ℃ and pressure below-0.08 MPa to obtain white solid 38.8g with purity of 99.38%. The HPLC and GC detection results are shown in Table 2, and the impurity D content and the solvent residue of the related substances are in accordance with the 2015 edition regulations of Chinese pharmacopoeia.

TABLE 2

Experimental example 2: taking 3000g of crude product of the compound a prepared in the embodiment 3, adding dimethyl sulfoxide, heating, dissolving, filtering, collecting filtrate, stirring absolute ethyl alcohol/purified water mixed solvent (volume ratio is 1:1), stirring, filtering, and vacuum drying filter cake at 45-55 ℃ under the pressure of < -0.08MPa to obtain a solid product. The content of the impurity D of the relevant substance was detected to be 0.37%, and the content of the residual solvent ethanol was 0.4721%.

Thus, the purification method of refining twice by using dimethyl sulfoxide/ethanol and dimethyl sulfoxide/ethanol water solution has better effect.

Test example 1:

the sample obtained in the foregoing experimental example 1 was examined by an X-ray powder diffractometer, and its XRPD pattern is shown in fig. 1, and its characteristic peak positions are shown in table 3 below:

TABLE 3 Table 3

Test example 2:

1. the stability of the sample obtained in the foregoing experimental example 1 under grinding, tabletting and heating conditions was examined:

a. taking 1g of a sample, grinding for 10min in a mortar under the protection of nitrogen, and scanning by an X-ray powder diffraction and differential scanning calorimeter;

b. 1g of a sample is taken, tiled, heated at 80 ℃ for 3 hours, and scanned by an X-ray powder diffraction and differential scanning calorimeter;

c. pressing a sample into tablets, and scanning by an X-ray powder diffraction and differential scanning calorimeter;

the results show that: comparing the obtained X-ray powder diffraction and differential scanning calorimeter scanning spectrum with the pre-treatment spectrum, and examining the change condition, wherein the result shows that the sample is stable under the conditions of grinding, heating and tabletting.

2. The stability of the samples was examined for 0-30 days at 25℃under RH90% + -5%:

the experimental result shows that the X-ray powder diffraction pattern and DSC pattern of the sample under the conditions are respectively consistent with the initial X-ray powder diffraction pattern and DSC pattern, so that the sample has good physical stability, and the maximum unknown single impurity and total impurity absolute value variation is smaller, so that the sample has good chemical stability.

3. Stability investigation of the investigated samples at 60℃under RH90% + -5%:

the experimental result shows that the X-ray powder diffraction pattern and DSC pattern of the sample under the conditions are respectively consistent with the initial X-ray powder diffraction pattern and DSC pattern, so that the sample has good physical stability, and the maximum unknown single impurity and total impurity absolute value variation is smaller, so that the sample has good chemical stability.

Claims (2)

1. A process for the preparation of (3 ar,5s,6 as) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide, characterized in that it comprises:

a) Mixing a crude product of a compound (3 aR,5s,6 aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide with a solvent (I) dimethyl sulfoxide, stirring for dissolving or heating for dissolving;

b) Then adding a solvent (II) for crystallization, wherein the solvent (II) is at least one selected from methanol, ethanol, isopropanol and water;

c) Adding the solid obtained in the step b) into a solvent (III), stirring and dissolving or heating and dissolving, wherein the solvent (III) is dimethyl sulfoxide;

d) And adding a solvent (IV) for crystallization, wherein the solvent (IV) is a mixed solution of at least one of methanol, ethanol or isopropanol and water.

2. The process of claim 1, wherein the solvent (II) is selected from ethanol.

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